Imidazole compounds and their use

ABSTRACT

The application discloses benzimidazole derivatives, pharmaceutical preparations comprised the compounds, their preparation and use in the treatment of disorders of the Central Nervous System such as ischemia, migraine, epilepsia, psychosis, Parkinsonism and depression.

The present application is a continuation-in-part of our prior-filed co-pending application Ser. No. 07/720,021, filed Jun. 24, 1991, now abandoned as of Jun. 11, 1992.

The present invention relates to therapeutical active compounds and their use as well as to pharmaceutical preparations comprising the compounds. The compounds of the invention possess valuable activity as calcium channel blockers which make them useful in the treatment of anoxia, ischemia, psychosis and migraine for example.

It is well known that an accumulation of calcium (calcium overload) in the brain is seen after anoxia, ischemia, migraine and other hyperactivity periods of the brain, such as after epileptic convulsions. An uncontrolled high concentration of calcium in the brain cells is known to cause most of the degenerative changes connected with above diseases. Therefore compounds which can block the calcium channels of brain cells will be useful in the treatment of anoxia, ischemia, migraine, epilepsia and in the prevention of the degenerative changes connected with the same.

Compounds blocking the socalled L-type calcium channels in the central nervous system (CNS) will be useful for the treatment of the above disorders by directly blocking the calcium uptake in the CNS.

Further, it is well known that the socalled N-type of calcium channels are involved in the regulation of the neurotransmitter release. Compounds blocking the N-type of calcium channels will indirectly and very powerfully prevent calcium overload in CNS after the hyperactivity periods of the brain as described above by inhibiting the enhanced neurotransmitter release seen after such hyperactivity, and especially the neurotoxic enhanced glutamate release after such hyperactivity periods of the CNS. Furthermore, blockers of the N-type of calcium channels will dependent upon the selectivity of the compound in question inhibit the release of various other neurotransmitters such as aspartate, GABA, glycine, dopamine, serotonin and noradrenaline and therefore blockers of N-type of calcium channels may be useful in the treatment of psychosis, Parkinsonism, depression, epilepsia and other convulsive disorders.

It is an object of the present invention to provide compounds being able to block the L-type and/or the N-type calcium channels.

The invention then, inter alia, comprises the following, alone or in combination.

A method of treating a disorder of a mammal, including a human, which is responsive to the blockade of N-type and/or L-type of calcium channels, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound having the formula: ##STR1## wherein

R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;

R⁴, R⁵, R⁶, R⁷ independently of each other are hydrogen, halogen, CF₃, or CN;

R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched;

R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, phenyl, piperidyl, pyrrolidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof,

and the method as above wherein anoxia, ischemia, migraine, epilepsia, and the prevention of the degenerative changes connected with anoxia, ischemia, migraine, and epilepsia is treated,

and the method as above wherein psychosis, Parkinsonism, depression, epilepsia or other convulsive disorders are treated,

further a compound having the formula ##STR2## wherein

R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;

R⁴, R⁵, R⁶ and R⁷ independently of each other are hydrogen, halogen, CF₃ or CN;

R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched;

two of R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, or phenyl and the last of R¹², R¹³ and R¹⁴ is pyrrolidyl, piperidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) wherein R^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof,

and a compound as above which is 1-(2-hydroxy-5-phenyl-phenyl)-2-amino-benzimidazole,

and a compound as above which is 1-(2-methoxy-5-phenyl-phenyl)-2-amino-benzimidazole,

and a compound as above which is 1-(2-methoxy-5-phenyl-phenyl)-2-amino-5-trifluoromethyl-benzimidazole,

and a compound as above which is 1-(3-(1-piperidyl)-phenyl)-5-fluoro-2-amino-benzimidazole,

still further a pharmaceutical composition comprising as active ingredient an effective amount of a compound as first above,

further a method of preparing a compound having the formula ##STR3## wherein

R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;

R⁴, R⁵, R⁶ and R⁷ independently of each other are hydrogen, halogen, CF₃ or CN;

R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched;

two of R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, or phenyl and the last of R¹², R¹³ and R¹⁴ is pyrrolidyl, piperidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) wherein R^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof comprising:

a) reacting a compound having the formula ##STR4## wherein

R', R", R⁴, R⁵, R⁶, R⁷, and R¹⁵ have the meanings set forth above and wherein one of R¹², R¹³ and R¹⁴ is iodine and the other of R¹², R¹³ and R¹⁴ have the meanings set forth above, with R¹² --B(OH)₂, R¹³ --B(OH)₂ or R¹⁴ --B(OH)₂, wherein R¹², R¹³ and R¹⁴ have the meanings set forth above, to form a compound of the invention, or

b) reacting a compound having the formula ##STR5## wherein

R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ have the meanings set forth above, with cyanogen bromide, to form a compound of the invention,

and the method as above wherein 1-(2-hydroxy-5-phenyl-phenyl)-2-amino-benzimidazole is prepared, and the method as above wherein 1-(2-methoxy-5-phenyl-phenyl)-2-amino-benzimidazole is prepared,

and the method as above wherein 1-(2-methoxy-5-phenyl-phenyl)-2-amino-5-trifluoromethyl-benzimidazole is prepared,

and the method as above wherein 1-(3-(1-piperidyl)-phenyl)-5-fluoro-2-amino-benzimidazole is prepared,

as well as the use of a compound having the formula ##STR6## wherein

R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;

R⁴, R⁵, R⁶, R⁷ independently of each other are hydrogen, halogen, CF₃, or CN;

R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched;

R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, phenyl, piperidyl, pyrrolidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) wherein R^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof for the preparation of a medicament useful in the treatment of disorders of a mammal, including a human, responsive to the blockade of N-type and/or L-type of calcium channels,

and the use of a compound having the formula, ##STR7## wherein

R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;

R⁴, R⁵, R⁶, R⁷ independently of each other are hydrogen, halogen, CF₃, or CN;

R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched;

R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, phenyl, piperidyl, pyrrolidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof for the preparation of a medicament useful in the treatment of anoxia, ischemia, migraine, epilepsia, psychosis, Parkinsonism depression, and the prevention of the degenerative changes connected with anoxia, ischemia, migraine and epilepsia,

and the use of a compound having the formula ##STR8## wherein

R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;

R⁴, R⁵, R⁶ and R⁷ independently of each other are hydrogen, halogen, CF₃ or CN;

R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched;

two of R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, or phenyl and the last of R¹², R¹³ and R¹⁴ is pyrrolidyl, piperidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) wherein R^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof for the preparation of a medicament useful in the treatment of disorders of a mammal, including a human, responsive to the blockade of N-type and/or L-type of calcium channels.

Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, oxalate and the acetate.

Biology

A high influx of calcium from extracelluar compartments into neurons is seen after opening of voltage operated calcium channels. Such opening of calcium channels may be induced by depolarization of neuronal membranes.

A crude synaptosome preparation contains small vesicles surrounded by neuronal membranes, and it is possible to study an opening of the voltage operated calcium channels in such a preparation.

In the below described test influx of ⁴⁵ Ca into synaptosomes is studied under depolarized conditions. The effect of test substances on the depolarization induced calcium uptake can thus be studied.

Test Procedure

The cerebral cortex from a male Wistar rat is homogenized in 20 ml ice cold 0.32M saccharose. In the following steps the temperature is kept at 0° C. to 4° C. The homogenate is centrifuged at 1,000×g for 10 minutes and the supernatant recentrifuged for 20 minutes at 18,000×g. The obtained pellet is resuspended in 0.32M saccharose (10 ml per g of original tissue).

Aliquots of 0.05 ml of the hereby obtained synaptosome suspension are added to glass tubes containing 0.625 ml of a NaCl buffer (136 mM NaCl, 4 Mm KCl, 0.35 mM CaCl₂, 1.2 mM MgCl₂, 20 mM Tris HCl, 12 mM glucose, pH 7.4) as well as 0.025 ml of different test substances in 48% ethanol. These tubes are pre-incubated for 30 minutes on ice and thereafter for 6 minutes at 37° C.

⁴⁵ Ca uptake is initiated by addition to above glass-tubes of 0.4 ml ⁴⁵ CaCl₂ (specific activity: 29-39 Ci/g; 0.5 Ci per tube). For depolarized samples the 0.4 ml ⁴⁵ CaCl₂ contain KCl (145 mM) and for non-depolarized NaCl (145 mM). The samples are incubated for 15 seconds.

The ⁴⁵ Ca uptake is stopped by filtering through glass fibre filters, which are subsequently washed 3 times with an ice cold solution of 145 mM KCl, 7 mM EGTA and 20 mM Tris HCl, pH 7.4 (5.0 ml). The radioactivity on the filters are measured by liquid scintillation spectrometry. Experiments are performed in duplicate.

Sample preparation

Above test substances are dissolved in for example 10 ml 48% ethanol at a concentration of 0.44 mg/ml. Dilutions are made in ethanol. Test substances are tested at concentrations of 0.1, 0.3, 1, 3, 10 . . . μg/ml.

Results

The test value is given as IC₅₀, that is the concentration in μM of the test substances, which inhibit 50% of the potassium stimulated uptake of ⁴⁵ Ca. The uptake in potassium depolarized samples are corrected for basal uptake in non-depolarized samples. The IC₅₀ value is determined from a dose response curve.

The results obtained by testing selected compounds according to the invention are presented in below table

                  TABLE                                                            ______________________________________                                         Compound                IC.sub.50 (μM)                                      ______________________________________                                         2-(2,5-dimethoxyphenyl)-2-amino-5-                                                                     0.7                                                    trifluoromethyl-benzimidazole                                                  1-(2-hydroxy-5-chlorophenyl)-5-trifluoro-                                                              2.0                                                    methyl-2-amino-benzimidazole                                                   1-(5-(1-pyrrolidinyl)-phenyl)-2-amino-5-                                                               2.0                                                    fluoro-benzimidazole                                                           ______________________________________                                    

It has been found (electrophysiological studies using the patch-clamp technique as described by Hamill et al., Pflugers Arch. 391, 85-100 (1981)), that the compounds of the invention block the N-type of calcium channels. Several compounds block the N-type calcium channels in these studies at concentrations from 0.5-10 μM. Examples of such compounds are 1-(2-hydroxy-5-phenyl-phenyl)-2-amino-5-trifluoromethyl-benzimidazole, and 1-(2-methoxy-5-phenyl-phenyl)-2-amino-5-trifluoromethyl-benzimidazole. Therefore the compounds are useful in the treatment of anoxia, ischemia and migraine (see also WO 91/07980).

Further it has been found that the compounds of the invention, for example 1-(2-hydroxy-5-phenyl-phenyl)-2-amino-benzimidazole potently antagonize hypermotility in mice as induced by amphetamine or cocaine. This is in full accordance with the influence of N-type calcium channel blockers on transmitter release in the central nervous system. Therefore the compounds of the invention are useful as anti-psychotics.

Pharmaceutical Compositions

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

Method of Treating

Due to the high degree of activity the compounds of the invention may be administered to a subject, e.g., a living animal body, in need of alleviation, treatment, or amelioration of an indication which is sensitive to the activity or influence of the compounds of the present invention including sensitive to the Ca channel blocking properties of the compounds of the invention. The compounds of the invention are preferably administered in the form of an acid addition salt thereof, concurrently, simultaneously, or together with a pharmaceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether oral, rectal, or parenteral (including subcutaneous) route, in an effective amount. Suitable dosage ranges are 0.1-500 milligrams daily, preferably 1-100 milligrams daily, and especially 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preferences and experience of the physician or veterinarian in charge.

The following examples will illustrate the invention further, however they are not to be construed as limiting.

EXAMPLE 1

1-(2-Hydroxy-5-trifluoromethylphenyl)-2-amino-5-trifluoromethyl benzimidazole (1P). To a solution of 2P (4.17 g, 11.2 mmol) in a mixture of DMF and triethylamine was added cyanogen bromide (1.54 g, 14.6 mmol). The mixture was stirred for 26 h at room temperature and then diluted with water (150 ml), filtered, and neutralized with 2M aqueous sodium hydroxide. The product was filtered off and recrystallized from ethanol. Yield 430 mg, mp >360° C.

In addition to compounds 1A-1AG also 1-[1-(2-hydroxynaphtyl)]-2-aminobenzimidazole (mp 210° C.) was prepared according to example 1. The starting material in the former case was N-(2-aminophenyl)-1-amino-2-naphthol.

EXAMPLE 2

1-(2-hydroxy-5-phenyl-phenyl)-2-aminobenzimidazole (1AC). To a solution of 1H (100 mg, 0.32 mmol) in dry methylene chloride under nitrogen, was added BBr₃ (0.036 ml, 0.38 mmol). The mixture was stirred at room temperature for 2 h. Water was then added and the pH was adjusted to 7 by the addition of an aqueous solution of sodium carbonate. Extraction with methylene chloride and drying over MgSO₄ was followed by column chromatography on silica gel with methylene chloride/ethanol (25:1) as eluent.

Yield: 40 mg, 0.13 mmol, mp 259°-261° C.

EXAMPLE 3

2-Amino-4,5'-dichloro-2'-hydroxydiphenylamine (20). A solution of 30 (6.41 g, 21.5 mmol) in a mixture of THF (100 ml) and ethanol (200 ml) was hydrogenated over 5% palladium on charcoal (500 mg) at ambient pressure until the uptake of hydrogen ceased. The mixture was filtered through celite into a flask containing 2.5 ml conc. HCl. Evaporation to dryness gave the product as a dark solid.

Yield: 6.47 g, mp 250°-280° C. (dec.).

In addition to compounds 2A-2Z also N-(2-aminophenyl)-1-amino-2-naphthol (mp 239°-246° C.) was prepared according to example 3. The starting material in the former case was N-(2-nitrophenyl)-1-amino-2-naphthol.

EXAMPLE 4

2,5-Dimethoxy-2'-nitro-4'-trifluoromethyldiphenylamine (3N). To a solution of 2,5-dimethoxy aniline (20 g, 130 mmol) in dry DMF under nitrogen, was added 80% NaH in mineral oil (4.31 g, 143 mmol). The mixture was stirred at room temperature for 1 h and then 4-chloro-3-nitrobenzotrifluoride (29.45 g, 130 mmol) was added. After stirring overnight at room temperature the excess sodium hydride was destroyed by the addition of a small amount of water. Dilution with 0.3M aqueous HCl gave a crystalline product which was filtered off and washed, first with water and then with petroleum ether. The product was dissolved in methylene chloride and filtered through a short column of silica gel. After evaporation of the solvent an orange coloured crystalline solid remained.

Yield 15.33 g, mp 93°-95° C.

In addition to compounds 3A-3Z also N-(2-nitrophenyl)-1-amino-2-naphthol (mp 185°-188° C.) was prepared according to example 3. The starting material in the former case was 3-(2-nitrophenyl)benzo[e]benzoxazole-2-one.

EXAMPLE 5

4,5'-Bistrifluoromethyl-2'-hydroxy-2-nitrodiphenylamine (3P). To a solution of 4E (5.0 g, 12.75 mmol) in dimethoxy ethane was added 38.25 ml 1M aqueous NaOH. The mixture was stirred overnight. Dilution with water and neutralization with 1M HCl was followed by extraction with ether. Evaporation at room temperature gave an orange coloured oil that crystallized upon storage in the freezer.

Yield: 4.01 g, mp 120°-123° C.

EXAMPLE 6

1-(2-Methoxy-5-chlorophenyl)-2-dimethylamino-5-trifluoromethylbenzimidazole. To a solution of 1Q (0.5 g, 1.37 mmol) in ethanol was added K₂ CO₃ (0.38 g, 2.74 mmol) and iodometane (1.94 g, 13.7 mmol). The mixture was refluxed for 20 h, filtered, and evaporated to dryness. The product was purified by chromatography on silica gel with methylene chloride/methanol (9:1) as eluent. Yield 50 mg, mp 230°-234° C.

                  TABLE 1                                                          ______________________________________                                          ##STR9##                                                                                                                     Start-                                                                         ing                                                                            Materi-                         No   R1     R2    R3    R4    R5   R6    Mp/°C.                                                                        al                              ______________________________________                                         1A   H      H     OCH.sub.3                                                                            H     H    Cl    207-  2A                                                                       208                                   1B   CF.sub.3                                                                              H     OH    H     H    H     190-  2B                                                                       195                                   1C   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    Ph    227-  2C                                                                       231                                   1D   Cl     Cl    OCH.sub.3                                                                            H     H    Cl    222-  2D                                                                       224                                   1E   CF.sub.3                                                                              H     H     CF.sub.3                                                                             H    H     174-  2E                                                                       175                                   1F   CF.sub.3                                                                              H     H     OCH.sub.3                                                                            H    CF.sub.3                                                                             194-  2F                                                                       195                                   1G   CN     H     OH    H     H    Cl    250-  2G                                                                       254                                   1H   H      H     OCH.sub.3                                                                            H     H    Ph    234-  2H                                                                       238                                   1I   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    CF.sub.3                                                                             214-  2I                                                                       217                                   1J   CF.sub.3                                                                              H     H     Cl    H    H     221-  2J                                                                       224                                   1K   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    CH.sub.3                                                                             210-  2K                                                                       212                                   1L   H      H     OH    H     H    Cl    276-  2L                                                                       278                                   1M   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    F     180-  2M                                                                       184                                   1N   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    OCH.sub.3                                                                            192-  2N                                                                       194                                   1O   Cl     H     OH    H     H    Cl    286-  2O                                                                       288                                   1P   CF.sub.3                                                                              H     OH    H     H    CF.sub.3                                                                             >360  2P                              1Q   CF.sub.3                                                                              H     OH    H     H    Cl    292-  2Q                                                                       293                                   1R   CF.sub.3                                                                              H     H     H     CF.sub.3                                                                            H     220-  2R                                                                       222                                   1S   CF.sub.3                                                                              H     CF.sub.3                                                                             H     H    H     201-  2S                                                                       204                                   1T   CF.sub.3                                                                              H     H     Cl    Cl   Cl    208-  2T                                                                       210                                   1U   CF.sub.3                                                                              H     H     CF.sub.3                                                                             Cl   H     213-  2U                                                                       215                                   1V   CF.sub.3                                                                              H     H     I     H    H     190-  2V                                                                       193                                   1W   CF.sub.3                                                                              H     H     1-pyr.                                                                               H    H     239-  2W                                                                       241                                   1X   CF.sub.3                                                                              H     H     H     OPh  H     58-63 2X                              1Y   F      H     H     1-pip.                                                                               H    H     151-  2Y                                                                       153                                   1Z   CF.sub.3                                                                              H     H     OPh   H    H     177-  2Z                                                                       179                                   1AA  Cl     Cl    OH    H     H    Cl    >360  1D                              1AB  CF.sub.3                                                                              H     H     H     H    CH.sub.3                                                                             202-  1F                                                                       206                                   1AC  H      H     OH    H     H    Ph    259-  1H                                                                       261                                   1AD  CF.sub.3                                                                              H     OH    H     H    CH.sub.3                                                                             278-  1K                                                                       281                                   1AF  CF.sub.3                                                                              H     OH    H     H    F     230-  1M                                                                       232                                   1AG  CF.sub.3                                                                              H     OH    H     H    OH    149-  IN                                                                       151                                   ______________________________________                                          1-pyr. = 1pyrrolidino.                                                         1-pip. = 1piperidino.                                                          Compounds 1A-1Z were prepared according to example 1 and compounds 1AA-1A      according to example 2.                                                  

                  TABLE 2                                                          ______________________________________                                          ##STR10##                                                                                                                    Start-                                                                         ing                                                                            materi-                         No   R.sup.1                                                                               R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                              R.sup.5                                                                             R.sup.6                                                                              mp/°C.                                                                        al                              ______________________________________                                         2A   H      H     OCH.sub.3                                                                            H     H    Cl    156-  3A                                                                       168                                                                            (d)                                   2B   CF.sub.3                                                                              H     OH    H     H    H     200-  3B                                                                       220                                                                            (d)                                   2C   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    Ph    181-  3C                                                                       184                                   2D   Cl     Cl    OCH.sub.3                                                                            H     H    Cl    174-  3D                                                                       176                                   2E   CF.sub.3                                                                              H     H     CF.sub.3                                                                             H    H     184-  3E                                                                       186                                   2F   CF.sub.3                                                                              H     H     OCH.sub.3                                                                            H    CF.sub.3                                                                             167-  3F                                                                       169                                   2G   CN     H     OH    H     H    Cl    170-  3G                                                                       172                                   2H   H      H     OCH.sub.3                                                                            H     H    Ph    127-  3H                                                                       150                                                                            (d)                                   2I   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    CF.sub.3                                                                             177-  3I                                                                       180                                   2J   CF.sub.3                                                                              H     H     Cl    H    H     182-  3J                                                                       184                                   2K   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    CH.sub.3                                                                             148-  3K                                                                       151                                   2L   H      H     OH    H     H    Cl    245 (d)                                                                              3L                              2M   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    F     182-  3M                                                                       184                                   2N   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    OCH.sub.3                                                                            156-  3N                                                                       160                                   2O   Cl     H     OH    H     H    Cl    250-  3O                                                                       280                                   2P   CF.sub.3                                                                              H     OH    H     H    CF.sub.3                                                                             200-  3P                                                                       205                                   2Q   CF.sub.3                                                                              H     OH    H     H    Cl    202-  3Q                                                                       207                                   2R   CF.sub.3                                                                              H     H     H     CF.sub.3                                                                            H     163-  3R                                                                       165                                   2S   CF.sub.3                                                                              H     CF.sub.3                                                                             H     H    H     78-80 3S                              2T   CF.sub.3                                                                              H     H     Cl    Cl   Cl    216-  3T                                                                       218                                   2U   CF.sub.3                                                                              H     H     CF.sub.3                                                                             Cl   H     184-  3U                                                                       186                                   2V   CF.sub.3                                                                              H     H     I     H    H     182-  3V                                                                       185                                   2W   CF.sub.3                                                                              H     H     1-pyr.                                                                               H    H     210 (d)                                                                              3W                              2X   CF.sub.3                                                                              H     H     H     OPh  H     *     3X                              2Y   F      H     H     1-pip.                                                                               H    H     220 (d)                                                                              3Y                              2Z   CF.sub.3                                                                              H     H     OPh   H    H     180-  3Z                                                                       183                                   ______________________________________                                          1-pyr. = 1pyrrolidyl.                                                          1-pip. = 1piperidyl.                                                           * = Isolated in an impure state unsuitable for melting point                   determination.                                                           

                  TABLE 3                                                          ______________________________________                                          ##STR11##                                                                                                                    Start-                                                                         ing                                                                            materi-                         No   R.sup.1                                                                               R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                              R.sup.5                                                                             R.sup.6                                                                              mp/°C.                                                                        al                              ______________________________________                                         3A   H      H     OCH.sub.3                                                                            H     H    Cl    112-  c                                                                        113                                   3B   CF.sub.3                                                                              H     OH    H     H    H     *     4A                              3C   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    Ph    *     c                               3D   Cl     Cl    OCH.sub.3                                                                            H     H    Cl    *     c                               3E   CF.sub.3                                                                              H     H     CF.sub.3                                                                             H    H     80-82 c                               3F   CF.sub.3                                                                              H     H     OCH.sub.3                                                                            H    CF.sub.3                                                                             94-96 c                               3G   CN     H     OH    H     H    Cl    210-  4B                                                                       212                                   3H   H      H     OCH.sub.3                                                                            H     H    Ph    oil   c                               3I   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    CF.sub.3                                                                             86-88 c                               3J   CF.sub.3                                                                              H     H     Cl    H    H     92-94 c                               3K   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    CH.sub.3                                                                             106-  c                                                                        109                                   3L   H      H     OH    H     H    Cl    156-  4C                                                                       158                                   3M   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    F     131-  c                                                                        134                                   3N   CF.sub.3                                                                              H     OCH.sub.3                                                                            H     H    OCH.sub.3                                                                            93-95 c                               3O   Cl     H     OH    H     H    Cl    199-  4D                                                                       203                                   3P   CF.sub.3                                                                              H     OH    H     H    CF.sub.3                                                                             120-  4E                                                                       123                                   3Q   CF.sub.3                                                                              H     OH    H     H    Cl    179-  4F                                                                       181                                   3R   CF.sub.3                                                                              H     H     H     CF.sub.3                                                                            H     67-69 c                               3S   CF.sub.3                                                                              H     CF.sub.3                                                                             H     H    H     87-89 c                               3T   CF.sub.3                                                                              H     H     Cl    Cl   Cl    137-  c                                                                        140                                   3U   CF.sub.3                                                                              H     H     CF.sub.3                                                                             Cl   H     93-94 c                               3V   CF.sub.3                                                                              H     H     I     H    H     98-101                                                                               c                               3W   CF.sub.3                                                                              H     H     1-pyr.                                                                               H    H     oil   c                               3X   CF.sub.3                                                                              H     H     H     OPh  H     94-96 c                               3Y   F      H     H     1-pip.                                                                               H    H     oil   c                               3Z   CF.sub.3                                                                              H     H     OPh   H    H     oil   c                               ______________________________________                                          1-pyr. = 1pyrrolidyl.                                                          1-pip. = 1piperidyl.                                                           * = Isolated in an impure state unsuitable for melting point                   determination.                                                                 c = Prepared from commercially available or know anilines and                  2halo-1-nitrobenzenes.                                                   

                  TABLE 4                                                          ______________________________________                                          ##STR12##                                                                     No.         R.sup.1   R.sup.2                                                                               mp/°C.                                     ______________________________________                                         4A          CF3       H      *                                                 4B          CN        Cl     228-230                                           4C          H         Cl     121-123                                           4D          Cl        Cl     172-174                                           4E          CF3       CF3    154-156                                           4F          CF3       Cl     177-180                                           ______________________________________                                          * = Isolated in an impure state unsuitable for melting point                   determination.                                                            

We claim:
 1. A method of treating a disorder of a mammal, including a human, which is responsive to the blockade of N-type and/or L-type of calcium channels, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound having the formula: ##STR13## wherein R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;R⁴, R⁵, R⁶, R⁷ independently of each other are hydrogen, halogen, CF₃, or CN; R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched; R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ -alkyl which may be straight or branched, phenyl, piperidyl, pyrrolidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) wherein R^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof.
 2. The method of claim 1 wherein anoxia, ischemia, migraine, epilepsia, and the prefention of the degenerative changes connected with anoxia, ischemia, migraine, and epilepsia is treated.
 3. The method of claim 1 wherein psychosis, Parkinsonism, depression, epilepsia or other convulsive disorders are treated.
 4. A compound having the formula ##STR14## wherein R' and R" independently are hydrogen or C₁₋₄ -alkyl which may be straight or branched, or R' and R" together form an alkylene chain of 2-6 carbon atoms;R⁴, R⁵, R⁶ and R⁷ independently of each other are hydrogen, halogen, CF₃ or CN; R¹¹ is hydrogen, halogen, CF₃, hydroxy or OR^(I) wherein R^(I) is C₁₋₄ -alkyl which may be straight or branched; two of R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, CF₃, C₁₋₄ -alkyl which may be straight or branched, OH, OR¹⁶ wherein R¹⁶ is C₁₋₄ alkyl which may be straight or branched, or phenyl and the last of R¹², R¹³ and R¹⁴ is pyrrolidyl, piperidyl, or phenyl which may be substituted one or more times with halogen, CF₃, CN, C₁₋₄ -alkyl which may be straight or branched, OH, NO₂, CO₂ H, NH₂, OR^(II) wherein R^(II) is C₁₋₄ -alkyl which may be straight or branched, CO₂ R^(III) wherein R^(III) is C₁₋₄ -alkyl which may be straight or branched, NR^(IV) R^(V) wherein R^(IV) and R^(V) independently are hydrogen, C₁₋₆ -alkyl which may be straight or branched, acyl, or wherein R^(IV) and R^(V) together form an alkylene chain of 2-6 carbon atoms; R¹⁵ is hydrogen or together with R¹⁴ form an extra benzo ring; or a pharmaceutically acceptable addition salt thereof.
 5. A compound of claim 4 which is 1-(2-hydroxy-5-phenyl-phenyl)-2-amino-benzimidazole.
 6. A compound of claim 4 which is 1-(2-methoxy-5-phenyl-phenyl)-2-amino-benzimidazole.
 7. A compound of claim 4 which is 1-(2-methoxy-5-phenyl-phenyl)-2-amino-5-trifluoromethyl-benzimidazole.
 8. A compound of claim 4 which is 1-(3-(1-piperidyl)-phenyl)-5-fluoro-2-amino-benzimidazole.
 9. A pharmaceutical composition comprising as active ingredient an effective amount of a compound of claim 4 together with a pharmaceutically-acceptable carrier or diluent.
 10. A method of claim 1 wherein the compound is administered in the form of a pharmaceutical composition in which it is present together with a pharmaceutically-acceptable carrier or diluent. 